Postoperative pain of moderate to severe intensity is experienced by 20-30% of patients despite advances in surgical techniques and perioperative analgesic strategies. Furthermore, unrelieved postoperative pain is a common cause for unplanned hospital admission and contributes to suboptimal functional outcomes. The development of analgesics possessing novel mechanisms of action would have significant value in addressing these problems. Acute inflammation is characteristic of surgical wounds. Few analgesic therapies are directed specifically at reducing the intensity of the inflammatory process itself. The complement system is one component of the acute inflammatory process which is activated by surgical incisions. Two of the so-called split products of complement system activation, C3a and C5a;have prominent roles in supporting inflammation in many disease states. In wounds these molecules stimulate the production of additional algogenic inflammatory mediators, and act as chemoattractants to enhance leukocytic infiltration. The principal goal of this project is to determine how the complement system functions within incisional wounds to support nociceptive sensitization and inflammation. In the first specific aim the use of selective C3a and C5a receptor antagonists, null mutant mice single fiber nerve recordings, dorsal root ganglion neuron patch clamp electrophysiology and other approaches to determine if and where these fragments act to support nociception. In the second specific aim we will delineate alterations in primary afferent and spinal cord gene expression related to the role of complement in nociception. In the third aim we examine the roles C3a/C5a have in supporting incisional edema, cytokine production and leukocytic infiltration, and define the roles of cytokines whose production is supported by complement. The main benefit in terms of public health is to move us towards the point of conducting clinical trials examining the efficacy of complement receptor antagonists as analgesics. A number of complement activity modifying compounds are in late stage clinical trials, and translational projects arising from this work are likely. PUBLIC HEALTH RELEVANCE The main benefit in terms of public health is to move us towards the point of conducting clinical trials examining the efficacy of complement receptor antagonists as analgesics. A number of complement activity modifying compounds are in late stage clinical trials, and translational projects arising from this work are likely.